Neisseria meningitidis is a non-motile, Gram-negative diplococcus human pathogen. It colonises the pharynx, causing meningitis and, occasionally, septicaemia in the absence of meningitis. It is closely related to N. gonorrhoeae, although one feature that clearly differentiates meningococcus from gonococcus is the presence of a polysaccharide capsule that is present in all pathogenic meningococci.
N. meningitidis causes both endemic and epidemic disease. In the United States the attack rate is 0.6-1 per 100,000 persons per year, and it can be much greater during outbreaks [Lieberman et al. (1996) JAMA 275(19):1499-1503; Schuchat et al (1997) N Engl J Med 337(14):970-976]. In developing countries, endemic disease rates are much higher and during epidemics incidence rates can reach 500 cases per 100,000 persons per year. Mortality is extremely high, at 10-20% in the United States, and much higher in developing countries. Following the introduction of the conjugate vaccine against Haemophilus influenzae, N. meningitidis is the major cause of bacterial meningitis at all ages in the United States [Schuchat et al (1997) supra].
Based on the organism's capsular polysaccharide, 12 serogroups of N. meningitidis have been identified. The meningococcal vaccine currently in use is a tetravalent polysaccharide vaccine composed of serogroups A, C, Y and W135. Following the success of the vaccination against H. influenzae, however, conjugate vaccines against serogroups A and C have been developed Meningococcus B remains a problem, however. This serotype currently is responsible for approximately 50% of total meningitis in the United States, Europe, and South America. The polysaccharide approach cannot be used because the menB capsular polysaccharide is a polymer of α(2-8)-linked N-acetyl neuraminic acid that is also present in mammalian tissue. This results in tolerance to the antigen; indeed, if a response were elicited, it would be anti-self, and therefore undesirable. In order to avoid induction of autoimmunity and to induce a protective immune response, the capsular polysaccharide has, for instance, been chemically modified substituting the N-acetyl groups with N-propionyl groups, leaving the specific antigenicity unaltered [Romero & Outschoorn (1994) Clin Microbiol Rev 7(4):559-575].
Alternative approaches to menB vaccines have used complex mixtures of outer membrane proteins (OMPs), containing either the OMPs alone, or OMPs enriched in porins, or deleted of the class 4 OMPs that are believed to induce antibodies that block bactericidal activity. These vaccines are poorly characterised and are only effective against homologous strains. To overcome antigenic variability, multivalent vaccines containing up to nine different porins have been constructed [e.g. Poolman J T (1992) Infect. Agents Dis. 4:13-28]. Additional proteins to be used in outer membrane vaccines have been the opa and opc proteins, but none of these approaches have been able to overcome the antigenic variability [e.g. Ala'Aldeen & Borriello (1996) Vaccine 14(1):49-53]. The Norwegian National Institute of Public Health vaccine, however, is safe, elicits strain-specific immunity in children and adults, and is efficacious in preventing disease in adolescents [Fredriksen et al. (1991) NIPH Ann 14(2):67-80 & 107-123].
These vaccines are, however, poorly characterised, and the molecular basis for their efficacy and protection has not been dissected. It is an object of the present invention to define antigenic components of vaccines, to characterise them in order to allow better defined vaccines to be produced (e.g. acellular sub-unit vaccines), and to broaden the Neisseria strains against which immunity is elicited.